Intracellular receptors (IR) form a class of structurally related gene regulators known as "ligand dependent transcription factors" (R. M. Evans, Science, 240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell's DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist.
PR antagonists may be used in contraception. In this context they may be administered alone (Ulmann, et al, Ann. N. Y. Acad. Sci., 261, 248, 1995), in combination with a PR agonist (Kekkonen, et al, Fertility and Sterility, 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 96/19997, published Jul. 4, 1996). PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz, et al, Horm. Cancer, 283), pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy, et al, J. Clin. Endo. Metab., 76, 513, 1993) and endometriosis (Kettel, et al, Fertility and Sterility, 56, 402, 1991). PR antagonists may also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (U.S. Pat. No. 5,719,136). PR antagonists, such as mifepristone and onapristone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna, et al, Ann. N.Y. Acad. Sci., 761, 224, 1995).
Jones, et al, (U.S. Pat. No. 5,688,810) describe the PR antagonist dihydroquinoline A. ##STR2##
Jones, et al, described the enol ether B (U.S. Pat. No. 5,693,646) as a PR ligand. ##STR3##
Jones, et al, described compound C (U.S. Pat. No. 5,696,127) as a PR ligand. ##STR4##
Zhi, et al, described lactones D, E and F as PR antagonists (J. Med. Chem., 41, 291, 1998). ##STR5##
Zhi, et al, described the ether G as a PR antagonist (J. Med. Chem., 41, 291, 1998). ##STR6##
Combs, et al., disclosed the amide H as a ligand for the PR (J. Med. Chem., 38, 4880, 1995). ##STR7##
Perlman, et. al., described the vitamin D analog I as a PR ligand (Tet. Letters, 35, 2295, 1994). ##STR8##
Hamann, et al, described the PR antagonist J (Ann. N.Y. Acad. Sci., 761, 383, 1995). ##STR9##
Chen, et al, described the PR antagonist K (Chen, et al, POI-37, 16.sup.th Int. Cong. Het. Chem., Montana, 1997). ##STR10##
Kurihari, et. al., described the PR ligand L (J. Antibiotics, 50, 360, 1997). ##STR11##
Elliott (Smith Kline Beecham) claimed the generic indoline M as potential endothelin receptor antagonists (WO 94/14434). The patent does not claim indolines and lacks the appropriate 5-aryl substitution, i.e. CN and NO.sub.2. ##STR12##
wherein: R.sub.4 =H, Ar, R.sub.11, OH, 1-5 C alkoxy (opt. substd. by OH, OMe or halogen), --S(O).sub.q R.sub.11, N(R.sub.6).sub.2, XR.sub.11, halogen or NHCOR.sub.6 ; X=(CH.sub.2).sub.n, O, NR.sub.6 or S(O).sub.q ; n=0-6; q=0-2; R.sub.6 =H or 1-4 C alkyl; R.sub.11 =1-8 C alkyl, 2-8 C alkenyl or 2-8 C alkynyl (all optionally substituted); Ar=(i) optionally substituted phenyl or benzo-fused group of (a) or (b); or (ii) napthyl, indoyl, pyridyl, thienyl, oxazolindyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, pyrrolyl or pyrimidyl, all optionally substituted by one or more R.sub.1 or R.sub.2 groups. ##STR13##
U.S Pat. No. 5,521,166 (Grubb) teaches cyclophasic hormonal regimens comprising an antiprogestin and a progestin wherein the progestin is administered in the alternating presence and absence of an antiprogestin. The disclosed regimens also provide for use of an estrogen for a period of from 2 to 4 days to prevent breakthrough bleeding.